GB1577991A - Analogues of prost-5,10,138-trienoic acid and process for preparing them - Google Patents

Analogues of prost-5,10,138-trienoic acid and process for preparing them Download PDF

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GB1577991A
GB1577991A GB2609/78A GB260978A GB1577991A GB 1577991 A GB1577991 A GB 1577991A GB 2609/78 A GB2609/78 A GB 2609/78A GB 260978 A GB260978 A GB 260978A GB 1577991 A GB1577991 A GB 1577991A
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C405/00—Compounds containing a five-membered ring having two side-chains in ortho position to each other, and having oxygen atoms directly attached to the ring in ortho position to one of the side-chains, one side-chain containing, not directly attached to the ring, a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, and the other side-chain having oxygen atoms attached in gamma-position to the ring, e.g. prostaglandins ; Analogues or derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

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Description

(54) ANALOGUES OF PROSTA-5,10,13-TRIENOIC ACID AND PROCESS FOR PREPARING THEM (71) We, HOECHST AKTIENGESELLSCHAFT, a Body Corporate organised according to the laws of the Federal Republic of Germany, of 6230 Frankfurt (Main) 80, Postfach 80 03 20, Federal Republic of Germany, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:- This invention relates to prostanoic acid analogues, and to a process for their manufacture, and is an improvement in or modification of the invention claimed in our Patent Specification No. 1,575,896.
Patent Specification No. 1,575,896 describes and claims an optically active analogue of prostanoic acid of the general formula I
or a racemate thereof, in which: R' and R2 are different, one representing a hydrogen atom and the other a hydroxyl group, R3 represents-a saturated or unsaturated, straight or branched chain aliphatic hydrocarbon radical having up to 8 carbon atoms, a straight or branched chain o- formylalkyl radical having 2 to 8 carbon atoms or an -R6-CO-R7 radical in which -R6 is a straight or branched chain alkylene radical having to 6 carbon atoms and R7 is a straight or branched chain alkyl radical having 1 to 6 carbon atoms with the proviso that the total number of carbon atoms in the radical -R6-CO- R7 does not exceed 8, and the corresponding oximes, oxime ethers, ethylene glycol acetals and ethylene dithioglycol acetals thereof, a straight or branched chain o9- hydroxyalkyl radical having 2-8 carbon atoms, or a straight or branched chain carboxyalkyl radical having 2-8 carbon atoms, R4 and R5 together represent an oxygen atom or one represents a hydrogen atom and the other a hydroxyl group, and X represents a branched chain alkylene group having 2-5 carbon atoms, or a phenylene or
radical which may be substituted by one or more substituents selected from C1- C5-alkyl and C1-C5-alkoxy groups, halogen atoms and trifluoromethyl groups, or a
radical, and the salts thereof, especially physiologically tolerable salts, with an organic or inorganic base, and the esters thereof with aliphatic, cycloaliphatic or araliphatic alcohols having 1---8 carbon atoms, with the proviso that when X represents an optionally substituted phenylene or
group, R3 does not represent a saturated or unsaturated, straight or branched chain aliphatic hydrocarbon radical having up to 8 carbon atoms.
Patent Specification No. 1,575,896 also describes and claims a process for the manufacture of the compounds of formula I, their salts and their esters with up to 8 carbon atoms in the ester part.
The compounds described and claimed in Specification No. 1,575,896 have spasmogenic, bronchodilating, hypotensive, gastric juice secretion-inhibiting, luteolytic and abortifacient properties, and they can therefore be used as medicaments.
The present invention is based on the observation thaf compounds having an intensified and more differentiated pharmacological action are obtained when the allylic hydroxyl group on the carbon atom 15 of the compounds of the formula I claimed in our above Patent Specification is esterified with a lower carboxylic acid.
The surprising, differentiating and action-intensifying influence of esterification is particularly pronounced in the preparations having a hypotensive action.
The present invention accordingly provides an optically active prostanoic acid analogue of the general formula II
or a racemate thereof, in which R represents a hydrogen atom or a straight or branched chain alkyl group having up to 10 carbon atoms, R3 represents a saturated or unsaturated, straight or branched chain aliphatic hydrocarbon radical having up to 8 carbon atoms, a straight or branched chain - formylalkyl radical having 2 to 8 carbon atoms or an -R6-CO-R7 radical in which R8 is a straight or branched chain alkylene radical having 1 to 6 carbon atoms and R7 is a straight or branched chain alkyl radical having 1 to 6 carbon atoms with the proviso that the total number of carbon atoms in the radical -R6- CO-R7 does not exceed 8, and the corresponding oximes, oxime ethers, ethylene glycol acetals and ethylene dithioglycol acetals thereof, a straight or branched chain a;-hydroxyalkyl radical having 2-8 carbon atoms, or a straight or branched chain carboxyalkyl radical having 2-8 carbon atoms, R4 and R5 together represent an oxygen atom or one represents a hydrogen atom and the other a hydroxyl group, and X' represents a branched chain alkylene group having 2-5 carbon atoms, or a phenylene or
radical which may be substituted by one or more substituents selected from C1- C5-alkyl and C1-C5-alkoxy groups, halogen atoms and trifluoromethyl groups, or a
radical.
The invention also provides salts of the compounds of formula II especially the physiologically tolerable salts, and furthermore esters, especially with aliphatic, cycloaliphatic and araliphatic alcohols having I to 8 carbon atoms.
Of the meanings given for the symbol R3, C1-C5 alkyl radicals, especially methyl, ethyl, propyl and isobutyl groups are preferred, as are C2-C5-alkenyl radicals, especially the allyl radical. Particularly suitable a;-formylalkyl are the straight or branched chain C2-C5 a;-formyl radicals and oximes, oxime ethers, ethylene glycols and ethylene dithioglycol acetals thereof, especially the 3oxopropyl- and 2,2 - dimethyl - 3 - oxopropyl radicals; particularly suitable hydroxyalkyl radicals are straight chain or branched chain C2-C5 a; - hydroxyalkyl radicals, especially the 3-hydroxypropyl and the 2,2 - dimethyl - 3 hydroxypropyl radicals; and particularly suitable carboxyalkyl radicals are the straight or branched chain C2-C5-carboxyalkyl radicals, especially the 2carboxyethyl and the 2,2 - dimethyl - 2 - carboxyethyl radicals.
Preferred radicals X' are the ethylidene group, the isopropylidene and the isobutylidene group, a phenylene or
group which may be substituted in the ring by one our more groups selected from methyl, ethyl, methoxy and ethoxy groups, fluorine and chlorine atoms and trifluoromethyl groups. Especially preferred are isobutylidene and ethylidene groups, and the groups
Straight or branched chain alkyl groups having up to 4 carbon atoms are preferred for R.
The preferred salts are alkali metal salts, especially sodium and potassium salts, as will as the salts formed with organic bases, for e,xample,benzyl ammonium [(C6H5HH3], triethanol ammonium (H(C2H5dH)3) and morpholine, salts.
The present invention also provides a process for the production of an optically active compound of the general formula II or a racemate thereof, or an ester or a salt thereof, which comprises acylating with a carboxylic acid of the formula R-COOH, in which R is as defined above, or with a reactive derivative thereof, a compound of the general formula Ia
in which R' and R2 are different, one representing a hydrogen atom and theother a hydroxyl group, and X' and Ra are as defined above, or an ester thereof at the carboxyl group, and, if desired, carrying out any one or more of the following steps in any suitable order: (a) reducing a resulting compound of formula II or ester thereof in which R4 and R5 together represent an oxygen atom to the corresponding compound in which one of R4 and R5 represents a hydrogen atom and the other a hydroxyl group, (b) converting a resulting compound of formula II into a salt thereof, especially a physiologically tolerable salt, or converting a resulting salt into another salt or into the free acid, and (c) esterifying a resulting compound of formula II or transesterifying or hydrolysing a resulting ester.
The compound of formula Ia is preferably produced by a process as described and claimed in our Patent Specification No. 1,575,896.
Either a free carboxylic acid R-COOH or a reactive derivative thereof may be used as the acylating agent. If a carboxylic acid is used, the reaction is preferably carried out in that acid as solvent at a temperature of from 0 to 700 C. In some cases it is advantageous to buffer the reaction mixture in order to avoid secondary reactions. (Compare J. E. Pike, F. H. Lincoln and W. P. Schneider, J. Org. Chem.
34, 3553 (1969)).
A carboxylic acid halide or carboxylic acid anhydride may be used for the acylation, in which case the reaction is preferably carried out in an aprotic solvent in the presence of a base at a temperature of from 0 to 800 C. Moreover, it is also possible to react an alcohol of formula Ia with the appropriate ketene. This reaction is likewise generally carried out in an aprotic solvent at room temperature.
To produce a compound of the formula II in which one of the radicals R' and R2 denotes a hydroxyl group and the other denotes a hydrogen atom, a 9 - oxo 15 - acyloxy - prostatrienoic acid derivative prepared by the above process is reduced, especially by means of a complex hydride which is capable of reducing an oxo group without attacking ester and carboxyl groups.
The use of sodium borohydride in methanoMwater as solvent has proved particularly advantageous.
If desired, a free acid of the formula II can be converted to a salt or ester by any of the customary processes.
The compounds according to the invention have useful pharmacological properties, in particular, a hypotensive action which is markedly superior to that of the non-acylated starting compounds. The side-effects on smooth muscle, which are undesirable for the hypotensive action, have so far not been observed in the compounds of the present invention. Because of their pharmacological activity, the compounds according to the invention can be used as medicaments.
The present invention accordingly provides a pharmaceutical preparation which comprises, as active substance, an optically active compound of the general formula II or a racemate thereof, or a physiologically tolerable salt thereof or an ester thereof, in admixture or conjunction with a pharmaceutically suitable carrier.
The pharmaceutical preparation.may be in the form or an aqueous solution or suspension, or the active substance may be in solution or suspension in a pharmaceutically suitable organic solvent, for example, a monohydric or polyhydric alcohol, for example ethanol, ethylene glycol or glycerol, an oil, for example, sunflower oil or cod-liver oil, an ether, for example, diethylene glycol dimethyl ether, or a polyether, for example, a polyethylene glycol, or in the presence of another pharmaceutically suitable polymeric carrier, for example, polyvinylpyrrolidone.
The preparations may be in the form of infusion solutions or injection solutions, or in a form suitable for enteral administration, for example tablets, as well as formulations which can be applied locally, for example, creams, emulsions, suppositories, but especially aerosols. Unit dosage forms are generally preferred.
The pharmaceutical preparations may comprise one or more further pharmacologically active substances, especially dieretic agents, for example, Furosemide; antidiabetic agents, for example, Glycodiazine, Tolbutamide, Glibenclamid, Phenformin, Buformin and Metformin; circulatory preparations in the widest sense, for example, coronary dilators, for example, Chromonar and Prenylamine, hypotensive agents, for example, reserpine, a-methyldopa or Clonidine, and antiarrhythmic agents; agents which lower the lipid level; agents used in geriatric medicine; and other formulations which have an action on the metabolism; psychopharmacological agents, for example Chlordiazepoxide, Diazepam and Meprobamate; and also vitamins, and furthermore prostaglandins, and prostaglandin-like compounds as well as prostaglandin antagonists and inhibitors of the biosynthesis of prostaglandins, for example, non-steroid antiphlogistic agents.
The following Examples illustrate the invention. In the Examples, temperatures are expressed in degrees Celcius and ratios of solvents for chromatography are by volume.
Example 1 9 - Oxo - ISa - acetoxy - 16,16 - dimethyl 18 - oxa - prosta - cis - 5,10 - trans 13 - trienoic Acid 200 mg of 16,16 - dimethyl - 18 - oxaprostaglandin - A2 are taken up in 7.5 ml of formic acid which had been slightly buffered beforehand by the addition of 50 mg of sodium carbonate. The mixture is left to stand for one day at room temperature, moisture being excluded. It is then taken up in chloroform and the organic phase is extracted twice with water, dried and evaporated. The residue is purified by chromatography on silica gel using cyclohexane/ethyl acetate/glacial acetic acid 90/10/1.
110 mg of the desired product are obtained. Thin layer chromatography (cyclohexane/ethyl acetate/glacial acetic acid 60/40/1).
Rf~0.70.
NMR (60 MHz, CDCl3) (8 values).
8.1 singlet 1 H (--OO-CCO-H); 7.45 resolved doublet 1 H (CH=CH-C=O), 6.15 resolved doublet 1 H (=CH-C=O); 5.15-5.85 multiplet 4 H (olefinic protons), 3.9-4.4 multiplet 1 H (CH-OOCH), 3.25 quartet 2 H, J=7 Hz (CH2OCH2CH3), 3.1 singlet 2 H (CH2OEt), 0.9-2.6 remaining protons including singlets at 0.9 and 1.0 ppm ((CH3)2C) and a triplet at 1.15, J=7 Hz (CH2CH3).
Example 2 9-Oxo -15a -acetoxy -16,16 - dimethyl - 18 -oxa -prosta -as -5,10 -trans 13 - trienoic Acid 100 mg of 16,16 - dimethyl - 18 - oxa - PGA2 (prepared according to Patent Specification No. 1,575,896) are initially introduced into a small flask under nitrogen. 3 ml of acetic anhydride are then added dropwise in the course of t hour and 20 mg of potassium carbonate are added to the clear solution. The mixture is stirred for 10 hours at room temperature. The end of the reaction is detected by means of a thin layer chromatogram (silica gel-eluant: cyclohexane/ethyl acetate/glaciai acetic acid=60:40:1). After the reaction has ended, the reaction mixture is taken up in 40 ml of CHIC1, and eluted with 3 times 10 'ml H2O. The CHCI3 phase is dried with MgSO4 and concentrated. The residue is subjected to chromatography on silica gel (eluant as above).
The fractions 9-16 contain 68 mg of an almost colourless oil.
Rf=0.65.
Nuclear magnetic resonance (in CDCl3), a values, 0.9 and 1.0 singlets, 6 H in total, J=3 Hz ( > C(CH3)2); 1.15 triplet 3 H, J=7 Hz (CH2CH3); 1.5-2.6 multiplet 10 H (CH2, CH); 2.0 singlet 3 H (COCH2); 3.05 singlet 2 H (CH2-OCH2CH3); 3.25 quartet 2 H, J=7 Hz (-CH2-O-CH2-CH2); 3.84.3 multiplet 1 H (HC-O); 5.15-5.85 multiplet 4 H (olefinic protons); 6.15 resolved doublet 1 H (CH=CH-C=O); II 7.45 resolved doublet 1 H (CH=CH-C=O), and 7.5 broad singlet 1 H (--COOH).
WHAT WE CLAIM IS: 1. An optically active compound of the general formula II
or a racemate thereof, in which
**WARNING** end of DESC field may overlap start of CLMS **.

Claims (18)

  1. **WARNING** start of CLMS field may overlap end of DESC **.
    Example 1 9 - Oxo - ISa - acetoxy - 16,16 - dimethyl 18 - oxa - prosta - cis - 5,10 - trans
    13 - trienoic Acid 200 mg of 16,16 - dimethyl - 18 - oxaprostaglandin - A2 are taken up in 7.5 ml of formic acid which had been slightly buffered beforehand by the addition of 50 mg of sodium carbonate. The mixture is left to stand for one day at room temperature, moisture being excluded. It is then taken up in chloroform and the organic phase is extracted twice with water, dried and evaporated. The residue is purified by chromatography on silica gel using cyclohexane/ethyl acetate/glacial acetic acid 90/10/1.
    110 mg of the desired product are obtained. Thin layer chromatography (cyclohexane/ethyl acetate/glacial acetic acid 60/40/1).
    Rf~0.70.
    NMR (60 MHz, CDCl3) (8 values).
    8.1 singlet 1 H (--OO-CCO-H); 7.45 resolved doublet 1 H (CH=CH-C=O), 6.15 resolved doublet 1 H (=CH-C=O); 5.15-5.85 multiplet 4 H (olefinic protons), 3.9-4.4 multiplet 1 H (CH-OOCH), 3.25 quartet 2 H, J=7 Hz (CH2OCH2CH3), 3.1 singlet 2 H (CH2OEt), 0.9-2.6 remaining protons including singlets at 0.9 and 1.0 ppm ((CH3)2C) and a triplet at 1.15, J=7 Hz (CH2CH3).
    Example 2 9-Oxo -15a -acetoxy -16,16 - dimethyl - 18 -oxa -prosta -as -5,10 -trans
    13 - trienoic Acid 100 mg of 16,16 - dimethyl - 18 - oxa - PGA2 (prepared according to Patent Specification No. 1,575,896) are initially introduced into a small flask under nitrogen. 3 ml of acetic anhydride are then added dropwise in the course of t hour and 20 mg of potassium carbonate are added to the clear solution. The mixture is stirred for 10 hours at room temperature. The end of the reaction is detected by means of a thin layer chromatogram (silica gel-eluant: cyclohexane/ethyl acetate/glaciai acetic acid=60:40:1). After the reaction has ended, the reaction mixture is taken up in 40 ml of CHIC1, and eluted with 3 times 10 'ml H2O. The CHCI3 phase is dried with MgSO4 and concentrated. The residue is subjected to chromatography on silica gel (eluant as above).
    The fractions 9-16 contain 68 mg of an almost colourless oil.
    Rf=0.65.
    Nuclear magnetic resonance (in CDCl3), a values, 0.9 and 1.0 singlets, 6 H in total, J=3 Hz ( > C(CH3)2); 1.15 triplet 3 H, J=7 Hz (CH2CH3); 1.5-2.6 multiplet 10 H (CH2, CH); 2.0 singlet 3 H (COCH2); 3.05 singlet 2 H (CH2-OCH2CH3); 3.25 quartet 2 H, J=7 Hz (-CH2-O-CH2-CH2); 3.84.3 multiplet 1 H (HC-O); 5.15-5.85 multiplet 4 H (olefinic protons); 6.15 resolved doublet 1 H (CH=CH-C=O); II 7.45 resolved doublet 1 H (CH=CH-C=O), and 7.5 broad singlet 1 H (--COOH).
    WHAT WE CLAIM IS: 1. An optically active compound of the general formula II
    or a racemate thereof, in which
    R represents a straight or branched chain alkyl group having up to 10 carbon atoms, Ra3 represents a saturated or unsaturated, straight or branched chain aliphatic hydrocarbon radical having up to 8 carbon atoms, a straight or branched chain a;- formylalkyl radical having 2 to 8 carbon atoms or an -R6-CO-R7 radical in which R6 is a straight or branched chain alkylene radical having 1 to 6 carbon atoms and R7 is a straight or branched chain alkyl radical having 1 to 6 carbon atoms with the proviso that the total number of carbon atoms in the radical -R6- CO-R7 does not exceed 8, and the corresponding oximes, oxime ethers, ethylene glycol acetals and ethylene dithioglycol acetals thereof, a straight or branched chain a;-hydroxyalkyl radical having 2-8 carbon atoms, or a straight or branched chain carboxyalkyl radical having 2-8 carbon atoms, R4 and R5 together represent an oxygen atom or one represents a hydrogen atom and the other a hydroxyl group, and X' represents a branched chain alkylene group having 2-5 carbon atoms, or a phenylene or
    radical which may be substituted by one or more substituents selected from C1- C5-alkyl and C1-C5-alkoxy groups, halogen atoms and trifluoromethyl groups, or a
    radical, and the esters thereof.
  2. 2. A compound as claimed in Claim 1, wherein X' and R3a have the meanings given in Claim 1, with the proviso that when X' represents an optionally substituted phenylene or
    group, RB does not represent a saturated or unsaturated, straight or branched chain aliphatic hydrocarbon radical having up to 8 carbon atoms.
  3. 3. A compound as claimed in Claim 1, wherein X' represents the ethylidene group, the isopropylidene group, the isobutylidene group, a phenylene or
    group which may be substituted in the ring by one or more substituents selected from methyl, ethyl, methoxy and ethoxy groups, fluorine and chlorine atoms, and trifluoromethyl groups.
  4. 4. A compound as claimed in Claim 3, wherein X' represents a
    or
    group,
  5. 5. A compound as claimed in any one of Claims I to 4, wherein R3a represents a methyl, ethyl, propyl or isobutyl radical, an allyl radical, a 3-oxopropyl or 2,2 dimethyl - 3 - oxopropyl radical, a 3-hydroxypropyl or 2,2 - dimethyl - 3 hydroxypropyl radical, or a 2-carboxyethyl or 2,2 - dimethyl - 2 - carboxyethyl radical.
  6. 6. 9 - Oxo - 15A - formyloxy - 16,16 - dimethyl - 18 - oxa - prosta - cis 5,10 - trans - 13 - trienoic acid.
  7. 7. 9 - Oxo - l5 - acetoxy - 16,16 - dimethyl - 18 - oxo - prosta - cis 5,10 - trans - 13 - trienoic acid.
  8. 8. An ester of a compound as claimed in any one of Claims 1 to 6 with an aliphatic, cycloaliphatic or araliphatic alcohol having up to 8 carbon atoms.
  9. 9. A salt of a compound as claimed in any one of Claims I to 7.
  10. 10. A physiologically tolerable salt of a compound as claimed in any one of Claims 1 to 7.
  11. I I. A process for the production of an optically active compound of the general formula II as claimed in Claim 1, or a racemate thereof, or an ester or salt thereof, which comprises acylating with a carboxylic acid of the formula R COOH, in which R is as defined in Claim 1, or with a reactive derivative thereof, a compound of tghe general formula Ia
    in which R' and R2 are different, one representing a hydrogen atom and the other a hydroxyl group, and X' and R3a are as defined in Claim 1, or an ester thereof at the carboxyl group, and, if desired, carrying out any one or more of the following steps in any suitable order: (a) reducing a resulting compound of formula II or ester thereof in which R4 and R5 together represent an oxygen atom to the corresponding compound in which one of R4 and R5 represents a hydrogen atom and the other a hydroxyl group, (b) converting a resulting compound of formula II into a salt thereof, or converting a resulting salt into another salt or into the free acid, and (c) esterifying a resulting compound of formula II or transesterifying or hydrolysing a resulting ester.
  12. 12. A process as claimed in Claim 11, carried out substantially as described in Example 1 or Example 2 herein.
  13. 13. An optically active compound of the general formula II as claimed in Claim 1 or a racemate thereof, or an ester or salt thereof, whenever produced by a process as claimed in Claim 11 or Claim 12.
  14. 14. A pharmaceutical preparation which comprises, as active substance, an optically active compound of the general formula II as claimed in any one of Claims 1 to 7 or Claim 13, or a racemate thereof, or a physiologically tolerable salt thereof, or an ester as claimed in Claim 1 or any one of Claims 8, 9 and 13, in admixture or conjunction with a pharmaceutically suitable carrier.
  15. 15.'A pharmaceutical preparation as claimed in Claim 14, in a form suitable for enteral administration.
  16. 16. A pharmaceutical preparation as claimed in Claim 14, in a form suitable for parenteral administration.
  17. 17. A pharmaceutical preparation as claimed in Claim 16, in the form of an aerosol.
  18. 18. A pharmaceutical preparation as claimed in any one of Claims 14 to 17, in unit dosage form.
GB2609/78A 1977-01-21 1978-01-23 Analogues of prost-5,10,138-trienoic acid and process for preparing them Expired GB1577991A (en)

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DE19772702368 DE2702368A1 (en) 1977-01-21 1977-01-21 NEW PROSTAGLANDIN ANALOGS AND METHOD FOR THEIR PRODUCTION

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AU (1) AU3256178A (en)
BE (1) BE863206R (en)
DE (1) DE2702368A1 (en)
DK (1) DK29378A (en)
ES (1) ES466005A2 (en)
FI (1) FI780169A (en)
FR (1) FR2378008A2 (en)
GB (1) GB1577991A (en)
LU (1) LU78916A1 (en)
NL (1) NL7714520A (en)
NO (1) NO780226L (en)
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US4094899A (en) * 1972-06-02 1978-06-13 Pfizer Inc. Oxaprostaglandins
GB1545633A (en) * 1975-02-24 1979-05-10 American Cyanamid Co 11-deoxy substituted prostaglandins of the e and f series

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ZA78368B (en) 1979-01-31
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DE2702368A1 (en) 1978-08-03
NO780226L (en) 1978-07-24
BE863206R (en) 1978-07-24
ES466005A2 (en) 1978-10-01
FR2378008A2 (en) 1978-08-18
NL7714520A (en) 1978-07-25

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